This study tested whether sarcoplasmic-endoplasmic reticulum Ca²⁺ ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist, BQ123 (1 µM), completely relaxed constriction to 10 nM endothelin-1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 µM), a sarcoplasmic-endoplasmic reticulum Ca²⁺ ATPase inhibitor, during the plateau endothelin-1 constriction enhanced the constriction by ~30%. BQ123 relaxed the endothelin-1 plus cyclopiazonic acid constriction by only ~10%. In contrast, prazosin (1 µM), an -adrenergic receptor antagonist, still completely relaxed the 0.3 µM phenylephrine constriction in the presence of cycopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by ~30% while Ni²⁺ and 2-aminoethoxydiphenyl borate, non-selective cation channel and store operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmic-endoplasmic reticulum Ca²⁺ ATPase activity selectively decreases the ability of endothelin receptor antagonist to inhibit the endothelin A receptor. The decreased antagonism may be related to the opening of store operated channels and subsequent greater internalization of endothelin A receptor.